Gene inactivation and its implications for annotation in the era of personal genomics

Abstract

The first wave of personal genomes documents how no single individual genome contains the full complement of functional genes. Here, we describe the extent of variation in gene and pseudogene numbers between individuals arising from inactivation events such as premature termination or aberrant splicing due to single-nucleotide polymorphisms. This highlights the inadequacy of the current reference sequence and gene set. We present a proposal to define a reference gene set that will remain stable as more individuals are sequenced. In particular, we recommend that the ancestral allele be used to define the reference sequence from which a core human reference gene annotation set can be derived. In addition, we call for the development of an expanded gene set to include human-specific genes that have arisen recently and are absent from the ancestral set.

A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

“…Derived allele frequency distribution in the CEU population for raw and high-confidence LoF variants, compared to missense and synonymous coding variants. Inset, distribution of the proportion of SNVs in each class at low allele counts (1-5). B.…”

“…Comparison of reported LoF variants between published genomes is complicated by differences in sequencing technology, variant-calling algorithms and gene annotation sets between studies (4, 5), and by the expectation that LoF variants will be highly enriched for false positives. The basis for this predicted enrichment is that strong negative natural selection is expected to act against the majority of variants inactivating protein-coding genes, thereby reducing the amount of true variation at these sites relative to the genome average, while sequencing error is expected to be approximately uniformly distributed; as a result, highly functionally constrained sites should show lower levels of observed polymorphism and substantially higher false positive rates (4).…”

The Tissue-Specific lncRNA Fendrr Is an Essential Regulator of Heart and Body Wall Development in the Mouse

“…Such lncRNA:protein-coding gene neighbours are found throughout the genome (Cabili et al 2011) and this functional link may reveal a more general mechanism for the control of patterning and lineage commitment (Cabili et al 2011; Ulitsky et al 2011; Margueron et al 2011; Ørom et al 2010). …”

Animal models of human genetic diseases: do they need to be faithful to be useful?

“…As a rule, the choice of the ''best'' specific allele at a given locus with the aim of modeling a human diseases should be made only after the structural description of the mutation has been established precisely and all its consequences assessed at the expression level. For example, point mutations occurring in introns and altering the splicing process may be dangerous because they can lead to the transcription of proteins that are structurally and functionally distinct from the ''canonical'' one (Balasubramanian et al 2011).…”